SIRT1-activating butein inhibits arecoline-induced mitochondrial dysfunction through PGC1α and MTP18 in oral cancer

Bishnu Prasad Behera; Soumya Ranjan Mishra; Kewal Kumar Mahapatra; Shankargouda Patil; Thomas Efferth; Sujit Kumar Bhutia

doi:10.1016/j.phymed.2024.155511

SIRT1-activating butein inhibits arecoline-induced mitochondrial dysfunction through PGC1α and MTP18 in oral cancer

Phytomedicine. 2024 Mar 16:129:155511. doi: 10.1016/j.phymed.2024.155511. Online ahead of print.

Authors

Bishnu Prasad Behera¹, Soumya Ranjan Mishra¹, Kewal Kumar Mahapatra², Shankargouda Patil³, Thomas Efferth⁴, Sujit Kumar Bhutia⁵

Affiliations

¹ Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, 769008, Odisha, India.
² Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, 769008, Odisha, India; Current affiliation: Department of Agriculture and Allied Sciences (Zoology), C. V. Raman Global University, Bhubaneswar, 752054, Odisha, India.
³ College of Dental Medicine, Roseman University of Health Sciences, South Jordan, 84095, UT, USA.
⁴ Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, 55128 Mainz, Germany.
⁵ Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, 769008, Odisha, India. Electronic address: sujitb@nitrkl.ac.in.

PMID: 38723523
DOI: 10.1016/j.phymed.2024.155511

Abstract

Background: Mitochondrial dysfunction associated with mitochondrial DNA mutations, enzyme defects, generation of ROS, and altered oxidative homeostasis is known to induce oral carcinogenesis during exposure to arecoline. Butein, a natural small molecule from Butea monosperma, possesses anti-inflammatory, anti-diabetic, and anti-cancer effects. However, the role of butein in the mitochondrial quality control mechanism has not been illuminated clearly.

Purpose: This study aimed to explore the role of butein in preserving mitochondrial quality control during arecoline-induced mitochondrial dysfunction in oral cancer to curtail the early onset of carcinogenesis.

Methods: Cell viability was evaluated by MTT assay. The relative protein expressions were determined by western blotting. Immunofluorescence and confocal imaging were used to analyze the relative fluorescence and co-localization of proteins. Respective siRNAs were used to examine the knockdown-based studies.

Results: Butein, in the presence of arecoline, significantly caused a decrease in mitochondrial hyperpolarization and ROS levels in oral cancer cells. Mechanistically, we found an increase in COXIV, TOM20, and PGC1α expression during butein treatment, and inhibition of PGC1α blunted mitochondrial biogenesis and decreased the mitochondrial pool. Moreover, the fission protein MTP18, and its molecular partners DRP1 and MFF were dose-dependently increased during butein treatment to maintain mitochondria mass. In addition, we also found increased expression of various mitophagy proteins, including PINK1, Parkin, and LC3 during butein treatment, suggesting the clearance of damaged mitochondria to maintain a healthy mitochondrial pool. Interestingly, butein increased the activity of SIRT1 to enhance the functional mitochondrial pool, and inhibition of SIRT1 found to reduce the mitochondrial levels, as evident from the decrease in the expression of PGC1α and MTP18 in oral cancer cells.

Conclusion: Our study proved that SIRT1 maintains a functional mitochondrial pool through PGC1α and MTP18 for biogenesis and fission of mitochondria during arecoline exposure and could decrease the risk of mitochondria dysfunctionality associated with the onset of oral carcinogenesis.

Keywords: Butein; Carcinogenesis; MTP18; Mitochondrial pool; Oral cancer; PGC1α; SIRT1.